What does the "two-hit hypothesis" of retinoblastoma suggest?

The "two-hit hypothesis" of retinoblastoma suggests that children acquire one mutation at birth and another later in life. This model explains the genetic basis of this type of cancer, which predominantly affects the retina in young children.

In individuals with familial retinoblastoma, the first "hit" is a germline mutation present at birth, meaning that they inherit a mutated copy of the RB1 gene from one parent. This mutation significantly increases the risk of developing tumors because it eliminates one functional copy of the gene critical for regulating cell cycle progression and preventing uncontrolled cell growth. The second "hit" typically occurs later, often due to a somatic mutation in the remaining normal copy of the gene, leading to a loss of function that ultimately results in tumor formation.

This hypothesis is essential for understanding not only the hereditary nature of retinoblastoma but also the likelihood of sporadic cases where both mutations occur in the somatic cells, rather than being inherited. Recognizing that one mutation can be inherited and the other can happen as a spontaneous event provides insight into the mechanisms of tumorigenesis and underscores the importance of genetic screening and surveillance in affected families.